The main objective of this study is to identify the mechanism(s) by which tumor necrosis factor-?- (TNF??) induces hypersensitivity. TNF? has been identified as a pro-nociceptive, pro-inflammatory cytokine, and anti-TNF? agents are currently used to treat painful inflammatory conditions which may, in part, be due to modulation of nociceptive signaling. The mechanism by which TNF? modulates nociception remains unknown. Recent work has demonstrated TNF? modulation of the tetrodotoxin-resistant Na+ channel a subunit, Nav1.8. This channel is primarily found in sensory neurons that detect painful stimuli, the primary afferent nociceptors, and is capable of altering excitability of dorsal root ganglia (DRG) neurons, a mechanism that could underlie behavioral hypersensitivity. Therefore, this proposal aims to examine the role of Nav1.8 in TNF? -induced behavioral hypersensitivity, to determine whether TNF? modulates DRG excitability, and to identify the necessity of Nav1.8 in this process. To this end, the proposed experiments will test the necessity of Nav1.8 in TNF? -induced mechanical and thermal hypersensitivity in vivo by behavioral assessment of hypersensitivity in Nav1.8-/- and wild-type littermate mice after intraplantar injection of TNF?. Further, because increased excitability is a mechanism by which hypersensitivity can be maintained, TNF? modulation of DRG excitability in vitro will be examined. These experiments will measure TNF? -induced alterations in excitability and examine the role of p38 MAPK in this process. Finally, the proposed experiments will then test the necessity of Nav1.8 in TNF? -induced modulation of DRG excitability by electrophysiological assessment of various membrane and AP properties in Nav1.8-/- and wild type DRG neurons. In accordance with the mission of the NIH, these studies are part of the long-term objective of identifying new potential targets for the treatment of painful conditions by understanding the biological mechanisms that underlie these conditions. These experiments can lead to enhancements in the treatment of pain, which is a costly and debilitating condition affecting millions of people.????